The ability to respond to stress is an important basic adaptive mechanism; hypothalamic-pituitary-adrenal (HPA) activation is known to be a central feature of this response. Hyperresponsiveness and/or deficits in recovery of HPA activity following stress could have adverse behavioral and physiological consequences for the organism and thus hyperresponsiveness, as well as altered behavioral and immune responsiveness, particularly following exposure to stressors. The present proposal will investigate mechanisms mediating the effects of prenatal ethanol exposure on HPA regulation as well as the role of the HPA hormones in mediating the alterations in immune function seen in E offspring. The Specific Aims are 1) to explore further the mechanisms underlying the increased HPA activity observed in E animals. Experiments will test two possible and not incompatible hypotheses: a) that HPA hyper-responsiveness in E animals result, at least in part, from deficits in feedback regulation of the HPA axis. Experiments will examine effects of repeated exposure to restraint (increased HPA activity and feedback) and of adrenalectomy (adx, removal of the feedback signal) and corticosterone (CORT) replacement (restoration of the feedback signal) on plasma hormone levels, hypothalamic and pituitary gene expression, and hippocampal glucocorticoid receptor gene expression ND activation; b) that HPA hyper-responsiveness in E animals results, at least in part, from enhanced stimulatory input to the HPA axis. Experiments will examine effects of acute and repeated restraint stress and/or of adx and CORT replacement on hypothalamic and pituitary gene expression, corticotropin releasing fracture (CRF) and CRF1 receptor expression, and pituitary CRF binding protein expression. 2) to examine effects of prenatal ethanol exposure on immune function of offspring. Experiments will test the hypothesis that the HPA hyper-responsiveness induced by prenatal ethanol may mediate at least in part the adverse changes in immune competence of E animals. Experiments will examine the role of HPA hormones in mediating altered antibody responses, and the role of the transcription factor NF-kB in mediating possible CORT-induced immunosuppression. The proposed work will have relevance to our understanding of the adverse effects of prenatal ethanol on adaptive functioning in adulthood.